Abstract Acne dysbiosis is defined as microbial imbalance with the over-growth of Propionibacterium acnes (P. acnes) in the acne microbiome. We have demonstrated that Staphylococcus epidermidis (S. epidermidis), a probiotic bacterium co-existed with P. acnes in an acne lesion, can exploit the carbohydrate fermentation to produce short-chain fatty acids (SCFAs) and rein in the over-growth of P. acnes. In collaboration with Surface Bioadvances Inc. in San Diego, we have developed polyethylene glycol dimethacrylate (PEG-DMA), ?-Lactose monohydrate (ALM), and propargyl-PEG5-tetra-Ac-beta-D-glucose as selective fermentation initiators (SFIs) which can specifically intensify fermentation activity of S. epidermidis, but not P. acnes. In this proposal, we will synthesize various PEG-carbohydrate conjugates as SFIs and identify the most potent SFI for rebalancing the dysbiotic acne vulgaris. The effects of SFIs on the suppression of P. acnes growth and reduction of {P. acnes-induced inflammation} will be investigated. We have recently obtained acne biopsies in partnership with Dr. Tissa R. Hata, a Director of the Dermatology Clinical Trials Unit at University of California, San Diego (UCSD). These acne biopsies have been used to establish ex vivo acne explants. The effectiveness of SFIs on suppression of P. acnes growth and reduction of pro-inflammatory cytokines will be tested by using ex vivo acne explants. Three Specific Aims are proposed to verify our hypothesis. In Specific Aim 1, we will compare the differential potencies of PEG macromers and their carbohydrate conjugates as SFIs for S. epidermidis, and investigate the broad-spectrum capability of SFI fermentation in growth inhibition of various clinical P. acnes strains. In Specific Aim 2, we will determine the efficacy of SFI fermentation for treatment of different inflammatory stages of acne vulgaris, {and examine the effect of SFI fermentation on the bacterial abundance in the acne microbiome.} In Specific Aim 3, we will {compare the anti-P. acnes potency of SFIs with SCFAs,} and explore the possible anti-comedogenic or toxic activities of SFIs. We envision that SFIs are able to specifically intensify the probiotic ability of S. epidermidis, produce SCFAs to ?beat? out its competitor (P. acnes). {The use of SFI to initiate fermentation of probiotic S. epidermidis can avoid difficulty in determining how many SCFAs in a mixture can be formulated as anti-P. acnes agents.} When successful, the SFI will be {the first fermentation initiator that can edit/reshape dysbiotic microbiome without using live microorganisms such as live bacteria or bacteriophages.}